Anthracyclines have been an effective backbone of cancer therapies for decades. Despite consistent clinical benefit observed with anthracycline-based regimens in breast cancer, significant toxicities such as acute and/or chronic cardiac dysfunction associated with such treatment have limited more expansive therapeutic use. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity to some extent, they have failed to demonstrate clear-cut efficacy advantages and can involve other toxicities such as palmar-plantar erythrodysesthesia (hand foot syndrome). In an effort to improve upon efficacy of currently available anthracyclines, a new immunoliposomal formulation, MM-302, has been prepared that targets doxorubicin to HER2 (ErbB2)-overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin.
Doxorubicin (dox) is an anthracyline chemotherapeutic agent used to treat a variety of cancers. The use of doxorubicin is dose-limited by the cardiotoxicity of the drug. In order to address this problem, doxorubicin has been formulated as a pegylated liposomal preparation. Liposomal encapsulation of drugs enables delivery of potent cytotoxic drugs with an improved therapeutic index or therapeutic window. doxorubicin HCl liposome injection (DOXIL®) is a pegylated liposome-encapsulated (liposomal) form of doxorubicin. DOXIL is a commercial form of pegylated liposomal doxorubicin (PLD). DOXIL alters the tissue distribution and pharmacokinetic profile of doxorubicin. Use of DOXIL results in a significantly lower rate of left ventricular cardiac dysfunction and symptomatic congestive heart failure as compared to therapy with free doxorubicin, both alone and in combination with trastuzumab in anthracycline-naïve and previously treated patients. DOXIL® is approved for use to treat Kaposi's sarcoma, ovarian cancer, and multiple myeloma. Doxorubicin HCl liposome injection is also sold as CAELYX®.
Immunoliposomes are antibody (typically antibody fragment) targeted liposomes that provide advantages over non-immunoliposomal preparations because they are selectively internalized by cells bearing cell surface antigens targeted by the antibody. Such antibodies and immunoliposomes are described, for example, in the following U.S. patents and patent applications: US 2010-0068255, U.S. Pat. Nos. 6,214,388, 7,135,177, and 7,507,407 (“Immunoliposomes that optimize internalization into target cells”); U.S. Pat. No. 6,210,707 (“Methods of forming protein-linked lipidic microparticles and compositions thereof”); U.S. Pat. No. 7,022,336 (“Methods for attaching protein to lipidic microparticles with high efficiency”) and US 2008-0108135 and U.S. Pat. No. 7,244,826 (“Internalizing ErbB2 antibodies.”). The following US and international patents and patent applications describe assays, cell lines, and related technologies that are relevant to this disclosure: U.S. Pat. No. 7,846,440 (“Antibodies against ErbB3 and uses thereof”) and U.S. Ser. No. 12/757,801, PCT/US2009/040259, and PCT/US2009/60721 (“Human Serum Albumin Linkers and Conjugates Thereof”).
Immunoliposomes targeting ErbB2 (HER2) can be prepared in accordance with the foregoing patent disclosures. Such HER2 targeted immunoliposomes include MM-302, which comprises the F5 anti-HER2 antibody fragment and contains doxorubicin. MM-302 contains 45 copies of mammalian-derived F5-scFv (anti-HER2) per liposome. The F5-scFv was selected for its ability to internalize while not affecting HER2 signaling. Characterization of the F5-scFv indicates that it does not cross react with mouse, rat or rabbit HER2 and does not interfere with HER2 signaling in the free scFv form. Because cardiomyocytes are known to express HER2, concerns have been expressed regarding the potential cardiotoxicity of MM-302 and related HER2-targeted immunoliposomes.
Dosage and Administration of Commercially Available Liposomal Doxorubicin:
DOXIL® (doxorubicin HCl liposome injection) is an exemplary liposomal anthracycline chemotherapeutic drug. DOXIL is typically administered intravenously at a dose indicated in mg/m2 and characterized as doxorubicin HCl equivalent (dox equiv., meaning the total mass of doxorubicin in each dose). Each dose is typically administered at an interval measured in weeks, to yield a dosage of x mg/m2 (dox equiv.) every y weeks. The first liposomal doxorubicin dose is typically administered at an initial rate of 1 mg/min to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate is typically increased to complete the administration of the drug over one hour.
Patients with Ovarian Cancer:
DOXIL is typically administered to ovarian cancer patients intravenously at a dose of 50 mg/m2 dox equiv. The patient is typically dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity and continues to tolerate treatment. A minimum of 4 courses is recommended because median time to response in clinical trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis, or hematologic toxicity the doses may be delayed or reduced. Pretreatment with or concomitant use of antiemetics should be considered.
Patients with AIDS-Related Kaposi's Sarcoma (KS):
DOXIL is typically administered to KS patients intravenously at a dose of 20 mg/m2 (dox equiv.). In KS patients the dose is typically repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment.
Patients with Multiple Myeloma:
To treat patients with multiple myeloma, DOXIL is administered with VELCADE® (bortezomib). Bortezomib is administered at a dose of 1.3 mg/m2 as intravenous bolus on days 1, 4, 8 and 11, every three weeks. DOXIL is typically administered to these patients at a dose of 30 mg/m2 as a 1-hr intravenous infusion following each day 4 bortezomib administration. Patients are typically treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.
HERCEPTIN® (trastuzumab) is a therapeutic anti-HER2 antibody that is very widely used to treat HER2 overexpressing tumors. A key dosage-limiting effect of trastuzumab is cardiotoxicity. Cardiomyocytes are known to express HER2, and trastuzumab-mediated cardiotoxicity is generally accepted as being caused by damage to HER2-expressing cardiomyocytes resulting from trastuzumab binding to the cardiomyocyte-expressed HER2—see, e.g., Hysing J and Wist E, “Cardiotoxic Effects of Trastuzumab,”. Tidsskr Nor Laegeforen, 2011 Nov. 15; 131(22):2239-2241. Anthracycline drugs such as doxorubicin are known to exert dose-limiting cardiotoxic effects, which are considered a major limitation in their use—see, e.g., Sawyer et al., “Mechanisms of Anthracycline Cardiac Injury: Can we identify strategies for cardio-protection?” Prog Cardiovasc Dis., 2010 September-October; 53(2):105-13.
Doxorubicin-induced cardiac damage is irreversible, resulting in acute injury and also damage that can manifest itself years after treatment. Exposure to cumulative concentrations of doxorubicin above 550 mg/m2 increases the potential for cardiomyopathy and heart failure. The development of HER2-directed therapy for the treatment of HER2-positive breast cancer has led to the investigation of the clinical benefit of the combination of doxorubicin and trastuzumab. The clinical efficacy of doxorubicin plus trastuzumab was superior to that of paclitaxel plus trastuzumab; however, there was an increased incidence of cardiac toxicity observed on the doxorubicin plus trastuzumab arm of the study, and the combination was not approved for marketing. The clinical benefit of anthracycline-based therapy, specifically in HER2-positive breast cancer, remains controversial.
Liposomal encapsulation of drugs has enabled delivery of potent cytotoxic drugs with an improved therapeutic index. Pegylated liposomal doxorubicin (PLD) alters the tissue distribution and pharmacokinetic profile of doxorubicin. PLD has demonstrated a significantly lower rate of left ventricular cardiac dysfunction and symptomatic congestive heart failure as compared to therapy with conventional doxorubicin, alone and in combination with trastuzumab in anthracycline-naïve and previously treated patients. A proposed mechanism for the reduced cardiotoxicity of PLD is that its greater size relative to conventional doxorubicin prevents it from crossing the endothelial barrier in the heart, thereby minimizing doxorubicin exposure to heart tissue.
MM-302 is a HER2-targeted, pegylated liposome designed to deliver doxorubicin directly to HER2-overexpressing cancers. HER2-targeted PLD deposits in tumors through the enhanced permeability and retention effect similar to PLD. In the tumor microenvironment, targeting HER2-overexpressing cells with HER2-targeted PLD results in superior efficacy relative to PLD in preclinical models. During the development of MM-302, concern was expressed by regulatory authorities that due to its HER2-targeting, MM-302 would deliver cardiotoxic doxorubicin directly to cardiomyocytes, resulting in increased cardiotoxicity compared to doxorubicin HCl liposome injection, and reduced dosages of MM-302 were suggested to avoid such life-threatening toxicities.